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Loss-of-function mutations in TDRD7 lead to a rare novel syndrome combining congenital cataract and nonobstructive azoospermia in humans.

Genetics in medicine : official journal of the American College of Medical Genetics (2019-05-03)
Yue-Qiu Tan, Chaofeng Tu, Lanlan Meng, Shimin Yuan, Calvin Sjaarda, Aixiang Luo, Juan Du, Wen Li, Fei Gong, Changgao Zhong, Han-Xiang Deng, Guangxiu Lu, Ping Liang, Ge Lin
ABSTRACT

Comorbid familial nonobstructive azoospermia (NOA) and congenital cataract (CC) have not been reported previously, and no single human gene has been associated with both diseases in humans. Our purpose was to uncover novel human mutations and genes causing familial NOA and CC. We performed whole-exome sequencing for two brothers with both NOA and CC from a consanguineous family. Mutation screening of TDRD7 was performed in another similar consanguineous family and 176 patients with azoospermia or CC alone and 520 healthy controls. Histological analysis was performed for the biopsied testicle sample in one patient, and knockout mice were constructed to verify the phenotype of the mutation in TDRD7. Two novel loss-of-function mutations (c.324_325insA (T110Nfs*30) and c.688_689insA (p.Y230X), respectively) of TDRD7 were found in the affected patients from the two unrelated consanguineous families. Histological analysis demonstrated a lack of mature sperm in the male patient's seminiferous tubules. The mutations were not detected in patients with CC or NOA alone. Mice with Tdrd7 gene disrupted at a similar position precisely replicated the human syndrome. We identified TDRD7 causing CC as a new pathogenic gene for male azoospermia in human, with an autosomal recessive mode of inheritance.

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GenomePlex® Single Cell Whole Genome Amplification Kit, Amplify genome of a single cell